The microtubule system of eukaryotic cells is an attractive target for the development of compounds useful in anticancer chemotherapeutics. Microtubules show highly dynamic instability and play an important role in cellular mitosis. Chemicals that attack microtubules through their major structural component, tubulin, disrupt or suppress both microtubule structure and normal functions by inhibition or promotion of microtubule assembly. Inihibition or arrest of cellular mitosis is the result.
One example of conventional antimitotic agents includes the vinca alkaloids, which inhibit microtubule polymerization. Another example of conventional antimitotic agents includes the taxoids, which promote microtubule assembly.
Colchicine is another conventional antimitotic agent. Although colchicine has limited medicinal application due to its high toxicity, it has played a findamental role in elucidation of the properties and functions of tubulin and microtubules.
Many natural products, such as cornigerine, podophyllotoxin, steganacin, and combretastatins, bind to the colchicine site of tubulin. Structurally, the compounds binding to this site are much simpler than those binding to vinca alkaloid or taxol domains. These compounds generally possess a "biaryl" system connected by a hydrocarbon bridge of variable length.
In the course of this group's search for novel plant-derived potent cytotoxic agents that are active against slow-growing solid tumors, we have isolated several flavonols as antitumor principles from a phytochemically and biologically heretofore uninvestigated plant, Polanisia dodecandra. Among these flavonols, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone showed remarkable cytotoxicity in vitro against panels of central nervous system, lung, ovarian, colon, and renal cancers and against melanoma and leukemia cell lines with GI.sub.50 values in the low micromolar to nanomolar concentration range. Flavonoids also possess the biaryl structural pattern of compounds binding to the colchicine site. We found that this compound is a strong inhibitor of tubulin polymerization with an IC.sub.50 value of 0.83.+-.0.2 .mu.M and to be a potent inhibitor of radiolabeled colchicine binding to tubulin, showing 59% inhibition when present in an equimolar concentration with colchicine.
Paralleled with our studies of plant antitumor agents, we synthesized a large series of 2-aryl-1,8-naphthyridiones, which are the amino analogs of cytotoxic antimitotic flavonoids, and found that many of these compounds were cytotoxic and possess activitity against tubulin polymerization and colchicine binding.
There remains a need in the art for cytotoxic agents for use in cancer therapy. There remains a need in the art for agents capable of inhibiting cellular mitosis for use in cancer therapy. Further there remains a need in the art for methods of treating cancer and methods of providing cancer therapy.